Genetic information improves the prediction of major adverse cardiovascular events in the GENEMACOR population

Abstract The inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies.

摘要 纳入遗传风险评分（genetic risk score, GRS）可改善冠状动脉粥样硬化性心脏病（coronary artery disease, CAD）的风险预测效能，较传统预测模型更具优势。但遗传信息对主要不良心血管事件（major adverse cardiovascular events, MACE）复发的预测价值仍存在争议。本研究针对GENEMACOR研究中的1587名CAD患者，对此前已报道与CAD相关的33个遗传变异进行基因分型。其中18个变异的风险比（hazard ratio, HR）>1，遂被用于构建加权遗传风险评分（weighted GRS, wGRS）。采用C统计量（C-Statistic）、净重新分类指数（Net Reclassification Index）及综合判别改善指数（Integrated Discrimination Improvement）评估MACE的判别与重新分类效能。将wGRS加入传统预测因子后，C指数从0.566提升至0.572（p=0.0003）。后续将wGRS加入传统及临床风险因子模型后，该模型的C指数从0.620小幅提升至0.622，且具有统计学显著性（p=0.004）。净重新分类指数显示，当基础模型结合wGRS时，17.9%的研究队列被更准确地重新分类。Kaplan-Meier估计量结果显示，在15年随访期间，携带更多风险等位基因的组别MACE发生率显著更高（p=0.011）。综上，在CAD患者中，相较于传统危险因素，加权遗传风险评分可改善MACE的风险预测、判别与重新分类效能，为制定更具成本效益的治疗策略提供依据。